Mycophenolate mofetil is the morpholinoethyl ester of mycophenolic acid; it has the following formula. ##STR1## Mycophenolate mofetil, the pharmaceutically acceptable salts thereof, and the immunosuppressive, anti-inflammatory, anti-tumor and anti-viral uses thereof are described in U.S. Pat. No. 4,753,935 ("the '935 Patent"), incorporated herein by reference.
An acid halide condensation route for synthesizing mycophenolate mofetil has been described in the '935 Patent. This synthetic method suffered from various deficiencies. The acid halide condensation route required a two-step process and necessitated the use of three (3) molar equivalents of 2-morpholinoethanol to give a yield of 85% mycophenolate mofetil, which included the formation of a dimeric impurity (2%), among others, requiring a recrystallization step. Color problems with the finished product were also associated with this synthetic method due to trace iron contamination considered secondary to corrosive conditions caused by thionyl chloride in the acid chloride step.
A carbodiimide route described in the '935 Patent has proven impractical for the synthesis of pharmaceutical grade mycophenolate mofetil due to an unacceptable percentage of impurities in the final product.
Those skilled in the field of esterification reactions will appreciate that the conventional teachings for synthesis of an ester through the reaction of an acid and an alcohol has required the use of a catalyst to achieve acceptable yields. See, for example, Morrison & Boyd "Organic Chemistry", Allyn and Bacon, Fifth Edition, pp. 841-843, 872-874. Catalytic reactions, however, entail the added cost of the catalyst and the additional steps of its addition and separation from the reaction mixture.
Thus, a non-catalytic alternative for synthesizing mycophenolate mofetil has been desired. It has surprisingly been discovered that good yields of mycophenolate mofetil can be obtained without the disadvantage of the prior described methods and without the use of a catalyst. Moreover, it has unexpectedly been discovered that the reaction of mycophenolic acid and 2-morpholinoethanol gives at least the equivalent or increased yields by omitting the use of a catalyst (i.e., use of a traditional catalyst does not increase or even slows the reaction). These, and other aspects of the present invention are described in greater detail below in the Summary and Detailed Description of the Invention.